CN106995445B - Bruton's tyrosine kinase inhibitor crystal form and preparation method thereof - Google Patents
Bruton's tyrosine kinase inhibitor crystal form and preparation method thereof Download PDFInfo
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Abstract
The invention provides a Bruton's tyrosine kinase inhibitor crystal form and a preparation method thereof. The crystal form is a crystal form A, and an X-ray powder diffraction pattern of the crystal form A has characteristic peaks at 2theta values of 5.6 degrees +/-2 degrees, 13.5 degrees +/-2 degrees, 16.0 degrees +/-2 degrees, 18.9 degrees +/-2 degrees, 21.2 degrees +/-2 degrees and 21.6 degrees +/-2 degrees. The solubility of the crystal form A in a biological medium is higher, so that the drug effect is improved, and the drug-loading rate is reduced. Has good stability, is not easy to deliquesce, and is convenient for long-term storage and placement of the medicine. And the preparation process of the crystal form A is simple to operate and low in cost, and has important value for the optimization and development of the medicine in the future.
Description
Technical Field
The invention relates to the field of chemical medicine, in particular to a Bruton's tyrosine kinase inhibitor crystal form and a preparation method thereof.
Background
The Bruton's Tyrosine Kinase (BTK) inhibitor 1- [ (3R) -3- [ 4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl ] -1-piperidyl ] -2-propen-1-one is jointly developed and developed by Pharmacyclics and Qiangsheng company, and is approved to be sold on the market at 11 months in 2013 by the American food and drug administration under the trade name of Imbruvica and Ibrutinib. It is an innovative oral drug named as a Bruton's Tyrosine Kinase (BTK) inhibitor, and is mainly used for treating Mantle Cell Lymphoma (MCL), a rare invasive blood cancer. The drug can irreversibly inhibit BTK through selective covalent binding with cysteine residue of active site of target protein Btk, thereby effectively preventing tumor from migrating from B cell to lymphoid tissue adapted to tumor growth environment. Previous analysts have predicted that the annual peak sales of ibbrutinib will reach around $ 50 billion for all indications, the largest share of which may come from chronic lymphocytic leukemia indication (CLL), which is also currently awaiting FDA approval.
Polymorphism is widespread in medicine. Different crystal forms of the same drug have obvious differences in the solubility, melting point, density, thermal stability and the like, so that the stability, uniformity, bioavailability, curative effect and safety of the drug are affected to different degrees. Therefore, comprehensive and systematic polymorphic form screening is carried out in drug development, and the most suitable developed crystal form is selected, which is one of important research contents.
Disclosure of Invention
In view of the defects of the prior art, the invention provides a Bruton's Tyrosine Kinase (BTK) inhibitor 1- [ (3R) -3- [ 4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidine-1-yl ] -1-piperidyl ] -2-propylene-1-ketone crystal form and a preparation method thereof, wherein the Bruton's Tyrosine Kinase (BTK) inhibitor crystal form is a crystal form A, has higher solubility in biological media, is beneficial to improving the drug effect and reducing the drug loading; the preparation process is simple to operate, low in cost and has important value for optimizing and developing the medicine.
The specific technical scheme of the invention is as follows:
crystalline form a of the Bruton's Tyrosine Kinase (BTK) inhibitor 1- [ (3R) -3- [ 4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl ] -1-piperidinyl ] -2-propen-1-one having characteristic peaks in the X-ray powder diffraction at 2theta values of 13.5 ° ± 0.2 °, 16.0 ° ± 0.2 °, 18.9 ° ± 0.2 °; the X-ray powder diffraction of the crystal form A has characteristic peaks at 2theta values of 5.6 +/-0.2 DEG, 21.2 +/-0.2 DEG and 21.6 +/-0.2 DEG; the differential scanning calorimetry analysis of the crystal form A has a characteristic melting peak at 158 +/-1 ℃; the crystalline forms are non-solvates or non-hydrates.
A method for preparing Bruton's Tyrosine Kinase (BTK) inhibitor 1- [ (3R) -3- [ 4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl ] -1-piperidinyl ] -2-propen-1-one crystalline form a, comprising the steps of:
a. dissolving: dissolving powder of 1- [ (3R) -3- [ 4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl ] -1-piperidinyl ] -2-propen-1-one in an organic solvent and slowly stirring to give a clear solution;
b. heating and refluxing: heating and refluxing the clear solution of the step a;
c. and (3) crystallization: slowly reducing the temperature for crystallization to obtain a crude crystal form A;
d. and (3) drying: and (5) after crystallization, carrying out vacuum drying.
Preferably, the organic solvent in step a is one of styrene, perchloroethylene, glacial acetic acid, trichloroethylene, an acetone/petroleum ether mixture, an acetone/n-pentane mixture, an acetone/n-hexane mixture, ethyl acetate, butyl acetate, ethylene glycol ether and triethanolamine; preferably, the organic solvent is selected from one of trichloroethylene, acetone/petroleum ether mixtures and butyl acetate.
Preferably, the organic solvent in step a is an acetone/petroleum ether mixture in any ratio.
Preferably, the ratio of the organic solvent to the- [ (3R) -3- [ 4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl ] -1-piperidyl ] -2-propen-1-one in the step a is 1-8: 1.
preferably, the heating reflux temperature in the step b is 40-50 ℃ and the time is 2-4 hours.
Preferably, the crystallization temperature in step c is: slowly reducing the temperature to 0-15 ℃; crystallization time: 5 to 8 hours.
Preferably, said step d comprises drying: the vacuum drying time is 8-13 h, and the drying temperature is 40-55 ℃.
Preferably, the preparation method comprises the following steps:
a, dissolving: dissolving powder of 1- [ (3R) -3- [ 4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl ] -1-piperidinyl ] -2-propen-1-one in an organic solvent and slowly stirring to give a clear solution;
b, refluxing: heating the clear solution in the step a to 40-50 ℃ and refluxing for 2-4 hours;
c, crystallizing: slowly reducing the temperature to 0-15 ℃ for crystallization for 5-8 hours to obtain a crude crystal form A;
d, drying: and after the crystallization is finished, carrying out vacuum drying for 8-13 h, wherein the drying temperature is 40-55 ℃.
Preferably, the preparation method comprises the following steps:
a, dissolving: dissolving a prescribed amount of a powder of 1- [ (3R) -3- [ 4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl ] -1-piperidinyl ] -2-propen-1-one in a prescribed amount of an organic solvent and slowly stirring to give a clear solution;
b, refluxing: heating the clear solution of step a to 45 ℃ and refluxing for 3 hours;
c, crystallizing: slowly reducing the temperature to 8 ℃ for crystallization for 7 hours to obtain a crude crystal form A;
d, drying: after the crystallization is finished, vacuum drying is carried out for 11 hours, and the drying temperature is 50 ℃.
Compared with the prior art, the preparation method of the crystal form A of the 1- [ (3R) -3- [ 4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl ] -1-piperidyl ] -2-propylene-1-one has the advantages that:
the preparation method of the crystal form provided by the invention is simple, has low cost, and has important value for the optimization and development of the medicine in the future. The preparation method has the purity of over 80.0 percent and the purity of over 99.7 percent.
Detailed Description
The invention will be further illustrated by the following specific examples, which are not intended to limit the scope of the invention. The skilled person can make modifications to the preparation method and the apparatus used within the scope of the claims, and such modifications should also be considered as the protection scope of the present invention. Therefore, the protection scope of the present patent shall be subject to the appended claims.
The starting materials or reagents used in the examples are commercially available.
Example 1
A process for the preparation of crystalline form a of 1- [ (3R) -3- [ 4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl ] -1-piperidinyl ] -2-propen-1-one:
(1) dissolving: 20.0g of a powder of 1- [ (3R) -3- [ 4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl ] -1-piperidinyl ] -2-propen-1-one are dissolved in 40mL of an acetone/petroleum ether mixture and slowly stirred to give a clear solution;
(2) refluxing: heating the clear solution of step (1) to 40 ℃ and refluxing for 4 hours;
(3) and (3) crystallization: slowly reducing the temperature to 0-5 ℃ for 5 hours of crystallization to obtain a crude crystal form A;
(4) and (3) drying: after the crystallization is finished, vacuum drying is carried out for 8 hours, and the drying temperature is 40 ℃. The yield was 88.8% and the purity was 99.96%.
Example 2
A process for the preparation of crystalline form a of 1- [ (3R) -3- [ 4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl ] -1-piperidinyl ] -2-propen-1-one:
(1) dissolving: 20.0g of a powder of 1- [ (3R) -3- [ 4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl ] -1-piperidinyl ] -2-propen-1-one is dissolved in 60mL of trichloroethylene and slowly stirred to give a clear solution;
(2) refluxing: heating the clear solution of the step (1) to 45 ℃ and refluxing for 3 hours;
(3) and (3) crystallization: slowly reducing the temperature to 5-7 ℃ for crystallization for 7 hours to obtain a crude crystal form A;
(4) and (3) drying: after the crystallization is finished, vacuum drying is carried out for 11 hours, and the drying temperature is 50 ℃. The yield is 88.6 percent, and the purity is 99.98 percent.
Example 3
A process for the preparation of crystalline form a of 1- [ (3R) -3- [ 4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl ] -1-piperidinyl ] -2-propen-1-one:
(1) dissolving: 20.0g of a powder of 1- [ (3R) -3- [ 4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl ] -1-piperidinyl ] -2-propen-1-one are dissolved in 80mL of ethyl acetate and slowly stirred to give a clear solution;
(2) refluxing: heating the clear solution of step (1) to 50 ℃ and refluxing for 4 hours;
(3) and (3) crystallization: slowly reducing the temperature to 4-6 ℃ for crystallization for 8 hours to obtain a crude crystal form A;
(4) and (3) drying: after the crystallization is finished, vacuum drying is carried out for 13h, and the drying temperature is 55 ℃. The yield is 88.7 percent, and the purity is 99.98 percent.
Example 4
A process for the preparation of crystalline form a of 1- [ (3R) -3- [ 4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl ] -1-piperidinyl ] -2-propen-1-one:
(1) dissolving: 20.0g of a powder of 1- [ (3R) -3- [ 4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl ] -1-piperidinyl ] -2-propen-1-one is dissolved in 140mL of triethanolamine and slowly stirred to give a clear solution;
(2) refluxing: heating the clear solution of step (1) to 50 ℃ and refluxing for 4 hours;
(3) and (3) crystallization: slowly reducing the temperature to 13-15 ℃ for crystallization for 8 hours to obtain a crude crystal form A;
(4) and (3) drying: after the crystallization is finished, vacuum drying is carried out for 13h, and the drying temperature is 55 ℃. The yield is 85.3 percent, and the purity is 99.93 percent.
Example 5
A process for the preparation of crystalline form a of 1- [ (3R) -3- [ 4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl ] -1-piperidinyl ] -2-propen-1-one:
(1) dissolving: 20.0g of a powder of 1- [ (3R) -3- [ 4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl ] -1-piperidinyl ] -2-propen-1-one are dissolved in 140mL of styrene and slowly stirred to give a clear solution;
(2) refluxing: heating the clear solution of step (1) to 50 ℃ and refluxing for 4 hours;
(3) and (3) crystallization: slowly reducing the temperature to 13-15 ℃ for crystallization for 8 hours to obtain a crude crystal form A;
(4) and (3) drying: after the crystallization is finished, vacuum drying is carried out for 13h, and the drying temperature is 55 ℃. The yield was 83.3% and the purity was 99.81%.
Example 6
A process for the preparation of crystalline form a of 1- [ (3R) -3- [ 4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl ] -1-piperidinyl ] -2-propen-1-one:
(1) dissolving: 20.0g of a powder of 1- [ (3R) -3- [ 4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl ] -1-piperidinyl ] -2-propen-1-one are dissolved in 140mL of perchloroethylene and slowly stirred to give a clear solution;
(2) refluxing: heating the clear solution of step (1) to 50 ℃ and refluxing for 4 hours;
(3) and (3) crystallization: slowly reducing the temperature to 13-15 ℃ for crystallization for 8 hours to obtain a crude crystal form A;
(4) and (3) drying: after the crystallization is finished, vacuum drying is carried out for 13h, and the drying temperature is 55 ℃. The yield was 84.0% and the purity was 99.78%.
Example 7
A process for the preparation of crystalline form a of 1- [ (3R) -3- [ 4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl ] -1-piperidinyl ] -2-propen-1-one:
(1) dissolving: 20.0g of a powder of 1- [ (3R) -3- [ 4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl ] -1-piperidinyl ] -2-propen-1-one are dissolved in 160mL of glacial acetic acid and slowly stirred to give a clear solution;
(2) refluxing: heating the clear solution of step (1) to 50 ℃ and refluxing for 4 hours;
(3) and (3) crystallization: slowly reducing the temperature to 13-15 ℃ for crystallization for 8 hours to obtain a crude crystal form A;
(4) and (3) drying: after the crystallization is finished, vacuum drying is carried out for 13h, and the drying temperature is 55 ℃. The yield was 83.4% and the purity was 99.81%.
Example 8
A process for the preparation of crystalline form a of 1- [ (3R) -3- [ 4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl ] -1-piperidinyl ] -2-propen-1-one:
(1) dissolving: 20.0g of a powder of 1- [ (3R) -3- [ 4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl ] -1-piperidinyl ] -2-propen-1-one are dissolved in 20mL of ethylene glycol ether and slowly stirred to give a clear solution;
(2) refluxing: heating the clear solution of step (1) to 50 ℃ and refluxing for 4 hours;
(3) and (3) crystallization: slowly reducing the temperature to 13-15 ℃ for crystallization for 8 hours to obtain a crude crystal form A;
(4) and (3) drying: after the crystallization is finished, vacuum drying is carried out for 13h, and the drying temperature is 55 ℃. The yield was 82.2% and the purity was 99.81%.
Example 9
A process for the preparation of crystalline form a of 1- [ (3R) -3- [ 4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl ] -1-piperidinyl ] -2-propen-1-one:
(1) dissolving: 20.0g of a powder of 1- [ (3R) -3- [ 4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl ] -1-piperidinyl ] -2-propen-1-one are dissolved in 140mL of butyl acetate and slowly stirred to give a clear solution;
(2) refluxing: heating the clear solution of step (1) to 50 ℃ and refluxing for 4 hours;
(3) and (3) crystallization: slowly reducing the temperature to 8-12 ℃ for crystallization for 8 hours to obtain a crude crystal form A;
(4) and (3) drying: after the crystallization is finished, vacuum drying is carried out for 13h, and the drying temperature is 55 ℃. The yield is 88.7 percent, and the purity is 99.98 percent.
Comparative example 1
Preparation of crystalline form a of 1- ((R) -3- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) piperidin-1-yl) prop-2-en-1-one (compound)
Amorphous compound (about 15mg) was weighed into a vial. And ten volumes (150 μ l) of solvent [ methyl tert-butyl ether (MTBE), diisopropyl ether (DIPE), ethyl acetate, isopropyl acetate, isopropanol, methyl isobutyl ketone (MIBK), Methyl Ethyl Ketone (MEK), acetone, methanol, nitromethane, 10% aqueous acetone or 10% aqueous isopropanol ] was added to the vial. The vial was sealed and placed in a shaker at 50 ℃ for 1 hour. If a slurry is obtained, an additional thirty times the volume (total 600. mu.l) of solvent is added and the slurry is returned to 50 ℃ for an additional hour. At this point, if the sample is still a slurry, no further solvent is added. The solution/slurry was stirred at 50 ℃ for 1 hour, then cooled to 0 ℃ at 0.1 ℃/min, and then kept at 0 ℃ overnight. Filtering the solid under vacuum to provide form a of the compound if a slurry is obtained; the solution was returned to ambient temperature to evaporate slowly through the pinhole to give form a of the compound. The yield is 48.4 percent, and the purity is 96.21 percent.
Comparative example 2
Amorphous compound (20mg) was added to a vial, followed by addition of solvent [ heptane (10 volumes), dioxane (1 volume), toluene (10 volumes), MTBE (10 volumes), DIPE (10 volumes), anisole (1 volume), ethyl acetate (10 volumes), isopropyl acetate (10 volumes), tetrahydrofuran (1 volume), DCM (1 volume), MIBK (10 volumes), MEK (10 volumes), acetone (10 volumes), methanol (10 volumes), ethanol (10 volumes), acetonitrile (10 volumes), nitromethane (1 volume), water (10 volumes), or 10% aqueous isopropanol (1 volume) ]. The sealed vial was placed in a maturation chamber (cycled between 50 ℃ and ambient temperature for 4 hours each) for 5 days, after which the solid was filtered under vacuum to provide form a of the compound. The yield was 43.2% and the purity was 93.53%.
Comparative example 3
In a clean round bottom flask, 12.0 grams of compound was dissolved in 120mL of methanol (aqueous acetone or ethanol or n-propanol) by heating to 45 ℃ under magnetic stirring. 72mL of water was added to the warm solution of dissolved compound over 45min, maintaining the internal temperature at 45 ℃. The solution slowly became a slurry and was stirred at elevated temperature for 3 hours. The slurry sample was aspirated, filtered and dried. The slurry was allowed to cool to room temperature and stirred for at least 16 hours. Another sample of the slurry was aspirated, filtered and dried. The solid was filtered and washed with 50mL of methanol: the 3:2 mixture of water was washed and dried on the filter for 40 hours. Resulting in crystal form a (melting point: first sample-152 ℃, second sample-154 ℃, main batch-154 ℃). The yield was 35.5% and the purity 94.14%.
Comparative example 4
A process for the preparation of crystalline form a of 1- [ (3R) -3- [ 4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl ] -1-piperidinyl ] -2-propen-1-one:
(1) dissolving: 20.0g of a powder of 1- [ (3R) -3- [ 4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl ] -1-piperidinyl ] -2-propen-1-one are dissolved in 80mL of methyl acetate and slowly stirred to give a clear solution;
(2) refluxing: heating the clear solution of step (1) to 50 ℃ and refluxing for 4 hours;
(3) and (3) crystallization: slowly reducing the temperature to 4-6 ℃ for crystallization for 8 hours to obtain a crude crystal form A;
(4) and (3) drying: after the crystallization is finished, vacuum drying is carried out for 13h, and the drying temperature is 55 ℃. The yield thereof was found to be 44.6%.
Comparative example 5
A process for the preparation of crystalline form a of 1- [ (3R) -3- [ 4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl ] -1-piperidinyl ] -2-propen-1-one:
(1) dissolving: 20.0g of a powder of 1- [ (3R) -3- [ 4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl ] -1-piperidinyl ] -2-propen-1-one are dissolved in 80mL of dichloromethane and slowly stirred to give a clear solution;
(2) refluxing: heating the clear solution of step (1) to 50 ℃ and refluxing for 4 hours;
(3) and (3) crystallization: slowly reducing the temperature to 6-8 ℃ for crystallization for 8 hours, and thus, a crude crystal form A cannot be obtained.
Claims (7)
1. A process for the preparation of crystalline form a of 1- [ (3R) -3- [ 4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl ] -1-piperidinyl ] -2-propen-1-one, characterized in that the process comprises the steps of:
a. dissolving: dissolving powder of 1- [ (3R) -3- [ 4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl ] -1-piperidinyl ] -2-propen-1-one in an organic solvent and slowly stirring to give a clear solution;
b. heating and refluxing: heating and refluxing the clear solution of the step a;
c. and (3) crystallization: slowly reducing the temperature for crystallization to obtain a crude crystal form A;
d. and (3) drying: vacuum drying is carried out after crystallization;
the organic solvent in the step a is selected from one of trichloroethylene, acetone/petroleum ether mixture and butyl acetate; the crystallization process in the step c is as follows: crystallization temperature: slowly reducing the temperature to 0-15 ℃; crystallization time: 5-8 hours;
the X-ray powder diffraction of the crystal form A has characteristic peaks at 2theta values of 5.6 degrees +/-0.2 degrees, 13.5 degrees +/-0.2 degrees, 16.0 degrees +/-0.2 degrees, 18.9 degrees +/-0.2 degrees, 21.2 degrees +/-0.2 degrees and 21.6 degrees +/-0.2 degrees; the differential scanning calorimetry analysis of the crystal form A has a characteristic melting peak at 158 +/-1 ℃; the crystalline forms are non-solvates or non-hydrates.
2. The method according to claim 1, wherein the organic solvent in step a is an acetone/petroleum ether mixture.
3. The preparation method according to claim 1, wherein the ratio of the organic solvent to the- [ (3R) -3- [ 4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl ] -1-piperidinyl ] -2-propen-1-one in step a is 1-8: 1.
4. the preparation method according to claim 1, wherein the heating reflux temperature in step b is 40-50 ℃ for 2-4 hours.
5. The method of claim 1, wherein step d comprises drying: the vacuum drying time is 8-13 h, and the drying temperature is 40-55 ℃.
6. The method of claim 1, comprising the steps of:
a. dissolving: dissolving a prescribed amount of a powder of 1- [ (3R) -3- [ 4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl ] -1-piperidinyl ] -2-propen-1-one in a prescribed amount of an organic solvent and slowly stirring to give a clear solution;
b. refluxing: heating the clear solution in the step a to 40-50 ℃ and refluxing for 2-4 hours;
c. and (3) crystallization: slowly reducing the temperature to 0-15 ℃ for crystallization for 5-8 hours to obtain a crude crystal form A;
d. and (3) drying: and after the crystallization is finished, carrying out vacuum drying for 8-13 h, wherein the drying temperature is 40-55 ℃.
7. The method of claim 1, comprising the steps of:
a. dissolving: dissolving a prescribed amount of a powder of 1- [ (3R) -3- [ 4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl ] -1-piperidinyl ] -2-propen-1-one in a prescribed amount of an organic solvent and slowly stirring to give a clear solution;
b. refluxing: heating the clear solution of step a to 45 ℃ and refluxing for 3 hours;
c. and (3) crystallization: slowly reducing the temperature to 8 ℃ for crystallization for 7 hours to obtain a crude crystal form A;
d. and (3) drying: after the crystallization is finished, vacuum drying is carried out for 11 hours, and the drying temperature is 50 ℃.
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